Tissue factor in COVID-19-associated coagulopathy

Abstract

Evidence of micro- and macro-thrombi in the arteries and veins of critically ill COVID-19 patients and in autopsies highlight the occurrence of COVID-19-associated coagulopathy (CAC). Clinical findings of critically ill COVID-19 patients point to various mechanisms for CAC; however, the definitive underlying cause is unclear. Multiple factors may contribute to the prothrombotic state in patients with COVID-19. Aberrant expression of tissue factor (TF), an initiator of the extrinsic coagulation pathway, leads to thrombotic complications during injury, inflammation, and infections. Clinical evidence suggests that TF-dependent coagulation activation likely plays a role in CAC. Multiple factors could trigger abnormal TF expression and coagulation activation in patients with severe COVID-19 infection. Proinflammatory cytokines that are highly elevated in COVID-19 (IL-1β, IL-6 and TNF-α) are known induce TF expression on leukocytes (e.g. monocytes, macrophages) and non-immune cells (e.g. endothelium, epithelium) in other conditions. Antiphospholipid antibodies, TF-positive extracellular vesicles, pattern recognition receptor (PRR) pathways and complement activation are all candidate factors that could trigger TF-dependent procoagulant activity. In addition, coagulation factors, such as thrombin, may further potentiate the induction of TF via protease-activated receptors on cells. In this systematic review, with other viral infections, we discuss potential mechanisms and cell-type-specific expressions of TF during SARS-CoV-2 infection and its role in the development of CAC.

Keywords: Antiphospholipid antibodies; C5a; COVID-19; DAMPs; PAMPs; Tissue factor; sepsis.

Fig. 1

Current concepts of TF in COVID-19-associated coagulopathy (CAC). Multiple mechanisms may contribute to TF expression, including direct infection of type I/II epithelial cells and monocytes, pattern-recognition receptors activation (TLR-3/-7/-8), complement-mediated MAC (C5b-C9) and anaphylatoxins (C5a, C3a), excessive cytokine release (IL-1, IL-6, IL-8, TNF-α) from immune and non-immune cells. These events subsequently lead to barrier dysfunction, increased vascular permeability, and activation of blood coagulation. Antiphospholipid antibodies may contribute to the activation of coagulation and endothelial cell-leukocyte interactions. TF-dependent activation of Xa/thrombin and excessive PAI-1 (which inhibits fibrinolysis) during SARS-CoV-2 infection results in the formation of fibrin-rich thrombi. IL, interleukin; NETs, neutrophil extracellular traps; vWF, von Willebrand factor; PAI-1, plasminogen activator inhibitor-1; TF, tissue factor; TNF-α, tumor necrosis factor-alpha; E-SELE, E-selectin; VCAM-1, vascular cell adhesion protein 1; ICAM-1, intercellular adhesion molecule-1; C3, complement 3; C5, complement 5; aPL antibody, antiphospholipid antibody.